OS10.7.A TUMOR-ASSOCIATED ASTROCYTES PROMOTE TUMOR PROGRESSION OF SONIC HEDGEHOG MEDULLOBLASTOMA BY SECRETING LCN2

Abstract

Abstract BACKGROUND Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB) accounts for about 25% of all subgroups of MB. Tumor microenvironment (TME) may play a key role in the tumor progression and therapeutic resistance. Tumor-associated astrocytes (TAAs) are reshaped to drive tumor progression through multiple paracrine signals. However, the mechanism by which TAAs modulate MB cells remains elusive. MATERIAL AND METHODS We explored the function of TAAs of SHH-MB in transgenic mouse model and co-culture system by a series of molecular biological techniques. To illuminate the TAAs distribution pattern during tumor progression of MB, we firstly detected MB transgenic mice bearing tumor at different time points by nuclear Magnetic resonance imaging (MRI). Histologic sections were then evaluated under microscope after H&E staining. The RNA-sequencing was also performed to evaluate differential expression between normal astrocytes (ASs) and tumor-associated astrocytes (TAAs). Bio-informatic analysis was followed to find the specific gene expressed in TAAs. Drug treatment of TAA inhibitor was finally applied in the animal model to clarify its effects on tumor progression. RESULTS We illuminated that TAAs showed a specific and dynamic pattern during SHH-MB development. Most TAAs gathered to the tumor margin during the tumor progression, rather than evenly distributed in the early-stage tumors and dissemination foci. We further demonstrated that LCN2 secreted by TAAs could promote the tumor growth and was correlated with the poor prognosis of MB patients. Knocking down LCN2 in TAAs in vitro impeded the proliferation and migration abilities of MB cells. In addition, we identified that TAAs accelerated the tumor growth by secreting LCN2 via STAT3 signaling pathway. Accordingly, blockade of STAT3 signaling by its inhibitor WP1066 in TAAs abrogated the effects of LCN2 on tumor progression in vitro and in vivo. CONCLUSION We for the first time clarified that LCN2, secreted by TAAs, could promote MB tumor progression via STAT3 pathway and has potential prognostic value. Our findings unveiled a new sight in reprogramming the TME of SHH-MB and provided a potential therapeutic strategy targeting TAAs.